HU219585B - Non ionic carboxamide derivative contrast materials, process for preparing them and radiographic contrast media containing them - Google Patents

Abstract

Triiodo-5-aminoisophthalamides in which the amino and one of the amide nitrogen groups are substituted are indicated. The compounds have at least two hydroxyl groups and low viscosity and osmolality. Processes for the preparation of the compounds are indicated.

Description

BACKGROUND OF THE INVENTION The present invention relates to novel nonionic contrast agents, to processes for their preparation and to radiological compositions containing them.

The X-ray contrast media used to visualize the heart, cardiovascular system and body cavities should be low viscosity, high solubility in water, non-toxic and high in iodine. Low viscosity is essential for rapid entry into the body, intermittent replacement of fast-flowing blood, such as angiocardiography or high-dose urography, and contrast enhancement during computed tomography. For the compound to be non-toxic, it needs to be highly hydrophilic, non-ionic and osmotically close to body fluids. While the previously described nonionic monomeric media have good bioavailability and viscosity, they have too high osmolality compared to body fluids. Generally, when used at a diagnostic effective concentration of 300 mg I / ml, they were well above physiological 310 mOsm. Excessive osmolality of the above solutions necessarily causes water to escape from the cells, destroying the cell membranes, disrupting total electrolyte balance in the body, and damaging the internal surface of blood vessels or other body cavities. In addition, it has been shown that too much osmolality is one of the causes of vascular pain that is always caused by contrast agents with too much osmolality.

Most of the nonionic contrast agents used, either in monomeric or oligomeric forms, are aromatic amides containing one or more polyhydroxy, lower aliphatic alkyl and acyl groups, attached to a nitrogen atom, and compounds containing cyclic carboxamides and amino groups. The triiodobenzene ring contains a number of functional groups that are close to each other in space. Many hydroxyalkylamines linked as amides have been described in the prior art. An example of such an amine is serinol; 1-amino-2,3-propanediol; N-methyl-1-amino-2,3-propanediol; aminotetritols; ethanolamine, diethanolamine, or triethanolamine.

Substituting the carboxyl groups at the 1- and 3-positions with the same hydroxyalkylamine represents a serious restriction on the design of the molecule, since the practicable substituents are either too small to provide solubility of the molecule or too large to make the solution small. viscosity [4,021,481 and

U.S. Patent No. 701,771 (Nycomed); U.S. Patent 4,547,357 (Schering);

U.S. Patent No. 1,013,323 to Bracco]. As a result, new improved compounds have been developed in which the two hydroxyalkylamines are different (U.S. Patent No. 4,361,921 to Schering). However, these compounds can be prepared by a complicated and expensive process.

U.S. Patent Nos. 3,701,771; 4,001,323; 4,021,481; 4,364,921; 4,554,357; and related U.S. Patent Nos. 214,663;

United States patent application filed July 1, 1988, describes various nonionic compounds for use as contrast agents.

The nonionic contrast agents of the present invention are asymmetric triiodoisophthalic acid diamide compounds wherein one carboxyl group is in the unsubstituted amide form, the other carboxyl group is in the form of at least mono (hydroxyalkyl) substituted amide, and the three iodine atoms and the two carboxyl substituents are free. a single ring carbon atom has a substituted nitrogen substituent. The molecule contains at least two hydroxyl groups.

The nonionic contrast agents of the present invention are acylamido-substituted triiodoisophthalic acid diamides wherein only one of the amide nitrogen atoms is substituted at least once. The compounds can be prepared by low cost, high yield and high purity.

The compounds of the present invention have low osmolality but also medium to low viscosity.

The present invention relates to novel compounds of formula I which contain at least 2 hydroxy groups

R 1 is hydrogen,

R ₂ is hydroxy (C 2 -C 6 alkyl) wherein the number of hydroxyl groups is 1- (nl) and n is the number of carbon atoms,

It is hydrogen or alkyl of 1 to 6 carbon atoms, optionally substituted with up to n-1 hydroxy groups, wherein n is the number of carbon atoms,

R ₃ is (C 1 -C 6) alkyl, (C 1 -C 6) hydroxyalkyl or (C 1 -C 6) alkoxy (C 1 -C 6) alkyl, or R ₃ is of formula (a) wherein R _b R ₂ and R ₄ are as defined above for 3- [N- (1,3-dihydroxy-2-propyl) carbamoyl] -5- (2-hydroxy-1-oxopropyl) amino-2,4-6 other than triiodobenzamide.

The latter compound has been previously described by S. Bradamante and G. Vittadini in Magn. Gap. in Chem., Vol. 25, p. 283 (1987)].

Alkyl groups may be straight or branched chain groups and generally straight chain groups which generally do not contain a quaternary carbon atom.

The alkyl groups of R ₂ mono- or polyhydroxyalkyl groups generally contain from 2 to 6 carbon atoms, usually from 2 to 4 carbon atoms. The groups preferably contain 1-5, usually 1-3 hydroxy groups. The hydroxyl groups can be primary, secondary or tertiary. Examples of such groups are tris (hydroxymethyl) methyl, hydroxyethyl, dihydroxypropyl and trihydroxybutyl. Ureas using 3-amino-1,2-propanediol, serinol or aminotetritols, i.e., threitol and erythritol, either as a mixture of D, L or in ethanolamine or diethanolamine or tromethamine or derivatives thereof in optically pure form, wherein the hydroxyl groups are reversibly protected - can be produced by using it.

HU 219 585 Β

The alkyl group of R ₃ preferably contains from 1 to 6 carbon atoms, usually from 1 to 4 carbon atoms, and is preferably methyl, hydroxymethyl or hydroxyethyl. Similarly, there may be an alkoxyalkyl group which preferably contains a C 1-3 alkoxy group, more preferably a C 1-2 group and a C 1-3 alkyl group such as methoxymethyl.

Alternatively, R ₃ may be a group of formula (a) containing 1 (methylene) or 2 (ethylene) -CH ₂ -; - (CH ₂ ) - ₂ - is preferably methylene.

R ₄ represents a hydrogen atom or an alkyl or mono or polyhydroxy alkyl group having preferably 1 to 6, usually 1 to 4 carbon atoms and includes methyl, ethyl, propyl, hydroxyethyl or dihydroxypropyl. Preferred monomeric compounds of the invention are, for example

5- [N- (2-hydroxyethyl) methoxyacetamido] -2,4,6-triiodo-3- [N- (1,3,4-trihydroxy-2-butyl) carbamoyl] benzamide; 5- [N- (2-hydroxyethyl) -hydroxy-acetamido] -2,4,6-trijód3- [N- (2,3-dihydroxypropyl) carbamoyl] benzamide;

5- [N- (2,3-dihydroxypropyl) acetamido] -2,4,6-triiodo-3- [N- (2,3-dihydroxypropyl) carbamoyl] benzamide;

5- [N- (2,3-dihydroxypropyl) -glikolamido] -2,4,6-trijód3- [N- (2-hydroxyethyl) carbamoyl] benzamide;

5- [N- (l, 3,4-trihydroxy-2-butyl) acetamido] -2,4,6-trijód3- [N- (2-hydroxyethyl) carbamoyl] benzamide;

5- (N-methyl-glycolamido) -2,4,6-triiodo-3- [N- (l, 3,4trihidroxi-erythro-2-butyl) carbamoyl] benzamide; and 5- [N- (2-hydroxyethyl) -acetamido] -2,4,6-triiodo-3- [N (1,3,4-trihydroxy-threo-2-butyl) -carbamoyl] -benzamide.

Preferred dimer compounds of the invention include bis [3- / N- (2,3-dihydroxypropyl) carbamoyl / 5-carbamoyl-2,4,6-triiodo-N- (2,3-dihydroxy) malonic acid. propyl) anilide];

malonic acid-bis [3- / N- (2,3-dihydroxypropyl) carbamoyl / -5karbamoil-2,4,6-triiodo-N- (2-hydroxyethyl) propionamide]; and malonic acid bis [3- (N- (1,3,4-trihydroxy-2-butyl) carbamoyl) -5-carbamoyl-2,4,6-triiodo-N-methylanilide).

The present invention also relates to novel radiological compositions containing a compound of formula I comprising a nonionic contrast agent of formula I wherein R _b R ₂ , R ₄ and R 3 are as defined above and a physiologically acceptable carrier. .

The radiological compositions of the present invention, which are primarily for diagnostic use, have a iodine content of about 50-52%, generally about 51%, a solution of 300 mg iodine / ml at 37 ° C and a viscosity of about 4-5 cps, and 300 mg iodine / ml. their osmolality in aqueous solution at 37 ° C is about 275-400, most often 285-375 mOsm, while in pharmaceutical formulations it is about 300-400, usually about 325-390.

The radiological compositions of the present invention may be prepared by a conventional method. The formulations generally contain an aqueous medium in which the calcium salt of a physiologically acceptable chelate complex, such as EDTA, and a pH of about 6.5 to about 7.5, in particular about pH 7, such as tris, carbonate, citrate or a mixture of these - is found. Other additives may include hydrogen carbonate, phosphate and the like. Calcium is present in the chelate at a concentration of about 5 to about 15, usually about 10 mg / 100 ml, while the buffer is generally present in an amount of about 2 to 10 mmol.

According to the present invention, the compounds of formula I can be prepared as follows:

a) a compound of formula V wherein R 1 and R ₂ are as defined above and the hydroxy group (s) in R ₂ optionally contains a protecting group (s) in a catalytic solvent, preferably pyridine, dimethylacetamide or dimethyl-; in formamide, with a compound of formula R ₃ COX wherein X is halogen or ester, and from the compound of formula I, wherein R ₄ is hydrogen, or the resulting R ₄ is CO ₃ , otherwise known as ( The protecting group (s) present in the intermediate of formula (I) are optionally removed and

R ₄ is for preparing compounds of formula (I) other than hydrogen of, if desired, salifying a compound having protective group (s) under basic conditions with an alkylating agent containing the R 4 group may be introduced to an alkylation reaction to give a, R ₄ represents the above substituent other than hydrogen ( Removal of any protecting group (s) present in the compound of formula (I), or

b) a compound of formula VI wherein R ₅ is hydrogen, R ₆ is R ₂ or hydrogen, X is halogen or ester forming group, with ammonia and if R ₆ is hydrogen, R Hydroxyalkylamine containing ₂ groups, the hydroxyl group (s) of which may optionally contain a protecting group (s), and the optional protecting group (s) is removed.

The compounds of formula I according to the invention may also be prepared by a combination of known processes. The compounds of the present invention may be prepared, for example, from compounds of formula II wherein R 1 and R ₂ are as defined above, and

X is a lower alkyl ester group or a halogen atom.

Compounds of formula (II) are prepared by reacting a hydroxyalkylamine of formula NHR, R ₂ , protected or unprotected, with a commercially available 5-nitroisophthalic acid monoester, and converting the remaining carboxyl group to an active derivative. For example, activation can be accomplished by forming a group wherein X is halogen, for example chlorine, bromine, iodine, or alkoxy, preferably chlorine or methoxy.

HU 219 585 Β

The 5-nitroisophthalic acid monoester can be aminated with the hydroxylamine NHR _t R ₂ as defined above, or it may first be subjected to aminolysis using ammonia. The remaining carboxyl group is then activated as described above. If the hydroxyl groups in the NR, R ₂ group are not protected and may react during activation, they may conveniently be protected in a conventional manner, for example by O-acetylation or isopropylidene derivatization.

The compounds of formula (II) may conveniently be crystallized from water or lower alkanols.

Prepared by asymmetric izoftálamidot reaction with anhydrous ammonia, or ammonium hydroxide, followed by hydrogenation trijódozzuk and acylated conventional reactions and the compound of formula (III) obtained, wherein in the formula RJM, R ₂ and R ₃ are as defined above . The reduction and iodination are carried out by conventional methods using a catalyst such as palladium on activated carbon or Raney nickel catalyst in water or lower alkanol using low pressure or high pressure hydrogen. The resulting 5-aminoisophthalic acid diamide is then iodinated by known methods. The resulting compound, after crystallization, is simply recovered from the reaction mixture, washed, dried and then acylated by known methods. For example, R ₃ activated acyl compounds of the formula CO-X where X is a hydrogen atom or the same acyl group which forms an anhydride, solvent and catalytic properties such as pyridine, dimethylacetamide or dimethylformamide is used.

When a compound of formula (I) wherein R ₄ is other than hydrogen is prepared, the alkylation may be carried out according to conventional procedures. Except for lower alkyl groups, which are suitably introduced into the molecule early in the synthesis, hydroxyalkylation is typically performed in the final step. Such alkylation is carried out in a high boiling point glycol solvent such as ethylene glycol or propylene glycol under very basic conditions such as sodium methoxide, sodium hydroxide or other organic or inorganic bases.

Alternatively, it may be advantageous for purification if the resulting by-products are difficult to remove later by conventional purification procedures, preserving a carboxyl group until the late step of the synthesis so that the compound is well soluble in water and subsequently precipitated using an inorganic acid. and we can drain again. Preferred salts are the ammonium, sodium, potassium, calcium, barium or lithium salts.

This alternative process is the reduction, iodination and acetylation of a compound of formula II (wherein X is hydroxy) to provide a compound of formula IV in the above reactions wherein R _b R ₂ and R ₃ are given above.

The hydroxyl groups are protected before activation of the carboxyl group. It is also necessary to diacetylate the anilide with R ₃ CO because this nitrogen atom would be adversely affected by the carboxyl activation reaction. The carboxyl group is activated as above. Acid chloride is the preferred activated derivative, but mixed anhydrides such as t-butoxycarbonyl may also be used. The compound of formula (IV) may conveniently be crystallized from an aprotic solvent and then reacted with ammonia or ammonium hydroxide, and the final step may be alkylation.

An effective amidation reaction requires an excess of an amidating base and an acid scavenger, or else requires the use of tertiary amines such as triethylamine, tributylamine, pyridine or inorganic bases such as bicarbonate or carbonate.

Other procedures may be used if undesirable by-products are expected to occur. In this case, the alkylation of the anilide can be carried out before the amidation. Alkylation of compounds of formula (IV) wherein R _b R ₂ and R ₃ are as described above may be carried out by known methods.

During the alkylation reaction introducing the R ₄ group, the protecting groups R ₃ CO are lost, so that the hydroxyl groups of the R _{2 group} (and where R ₄ is present) must be protected again before the carboxyl group is activated and subsequently amidated with ammonia. Acetyl groups are most often used for this purpose.

After the final reaction step, if the hydroxyl groups still contain a protecting group, such as when the alkylation reaction is not the last step, the protecting groups are suitably removed by standard procedures. For example, the product is reacted with an ion exchange resin or a catalytic amount of acid or base is used in an alcoholic or aqueous solvent.

Desalination may be carried out by known methods. For example, salts can typically be removed using an ion exchange resin. Columns containing mixed beds or separate anionic and separate cationic ion exchange resins can be used. Alternatively, the compound of formula (I) is absorbed on a polystyrene neutral resin and eluted therefrom.

After removal of the salts, the product can be crystallized from a variety of solvents, preferably lower alcohols.

The decolorization can be accomplished by refluxing with activated carbon in aqueous solution.

The dimer compound is readily prepared from benzamide in which the nitrogen atom of the amino group is alkylated and the remaining carbonyl group is activated, e.g. in the form of chlorocarbonyl. The diacid, in its activated form, is used, for example, as diacyl dichloride in an organic aprotic polar solvent. The chlorocarbonyl group bound to the ring carbon atom is then hydroxyalkylated and the final product is prepared.

The compounds of formula I according to the invention are stable in aqueous solution; they are easily formed from supersaturated ol4

EN 219 585 Β which is also stable. The solutions can be autoclaved by standard procedures. At a diagnostically appropriate concentration of iodine, the osmolytic properties of the compounds of the invention are very close to the physiological state. However, the viscosity of the solution is low. Therefore, the contrast agent of the present invention eliminates the earlier drawback that the two essential factors, low osmolality and low viscosity, are mutually exclusive. As a result, the new compounds have excellent local and systemic tolerance. The compounds have good bioavailability and high iodine content, especially when compared to currently available nonionic radiographic contrast agents.

By way of example, measured data for Compound 11 (Example 10), Compound 19 (Example 18), and Compound 41 (Example 39) are provided to illustrate the properties of the new benzamide derivatives. Data for prior art compounds are provided for comparison purposes.

Table I

Basic properties of nonionic monomeric X-ray contrast agents

Name or number of compound Iodine content as a percentage of molecular weight Viscosity 300 mg iodine / ml 37 ° C osmolality 300 mg iodine / ml solution Approximate limits iv- LD _S0 gjód / kg cPS Aqueous solution (mOsm) Formulated Pharmaceutical Solution (mOsm) Male mouse 16-20g Male rat 80-100 g iohexol 46 6.3 * 650 685 16-17 11.5-12.5 Iopamidoi 49 4.7 * 671 704 16-18 12-13 Iopromide 48 4.6 * 607 630 14-16 11-12 Ioxilan 48 4.7 560 588 16-18 12-13 (19) 51 4.1 365 390 14-16 13-14 (H) 51 4.2 300 326 15.5 to 16.5 15.5 to 17.5 (41) 52 3.5 314 322 16 to 17.5 15-17

* literature; other data were measured in our laboratory

All solutions are formulated, unless otherwise indicated.

The observed low osmolality and low toxicity have previously been achieved for only some non-ionic dimers but, due to their high viscosity, are generally not applicable in uroanography because at the same concentration they have at least twice the viscosity of the material of the present invention.

The novel compounds of the present invention exhibit excellent general biological tolerance. High osmolality causes vascular pain, and is a major side effect in cases where they want to imitate the vasculature of the outer limbs. (Sovak, M.: Current Contrast Media and Ioxilan, Comparative Evaluation of Vascular Pain by Aversion Conditioning, In vestigative Radiology, September 1988, Supp.). This is one of the most important diagnostic procedures in vascular radiology. The compounds of the present invention are expected to be substantially painless in similar procedures. By virtue of their physico-chemical and pharmacological properties, the compounds of the present invention are useful as water-soluble contrast agents for visualization of the urinary system and cardiovascular system, as well as for imaging body cavities and as a contrast agent for computed tomography. The present invention also encompasses novel diagnostic compositions of the formula (I) containing nonionic contrast media which contain, in addition to the contrast media, carriers and / or excipients customary in radiological compositions. These include, for example, injectable solutions of the compounds of the invention prepared by dissolving in water and adding standard physiologically compatible buffers and stabilizers, such as chelating agents. The compounds may also be administered via the intestinal tract if formulated with pharmaceutical carriers. The dimers are particularly suitable for use in spinal cord x-rays.

For vascular use, 20% to 80% w / v solutions of the compounds of the invention, preferably iodine concentrations of 150 to 400 mg / ml, may be used.

The following examples illustrate the invention.

Example 1

Amidation of 5-nitro-isophthalic acid monomethyl ester (1) with (threo) -2-amino-1,3,4-butanetriol and 5-nitro-3- [N (1,3,4-trihydroxytreo-but- 2-yl)] - carbamoylbenzoic acid

22.5 g (0.1 mol) of starting material (1) are mixed with 30.25 g (0.25 mol) of (threo) -2-amino-1,3,4-butanetriol and the suspension is heated at 110-120 ° C for 30 minutes. Heat to C. Complete conversion was monitored by TLC and the solution was poured into 200 mL of 1N hydrochloric acid. The product precipitates out as a precipitate. After cooling overnight, the product was filtered off and washed with ice water (2 x 20 mL). It is then dried in vacuo

This gave a white solid product ((2), 21.0 g, 67% yield).

Example 2

Esterification of 5-nitro-3- [N- (1,3,4-trihydroxytreo-but-2-yl)] - carbamoylbenzoic acid (2) with dimethyl sulfate and methyl 5-nitro-3- [N- ( Preparation of 1,3,4-trihydroxy-threo-but-2-yl) -carbamoyl] -benzoate (3)

15.7 g of compound (2) (0.05 mol) are dissolved in 55 ml of 1N sodium hydroxide solution and the solution is cooled to below 20 ° C. Dimethyl sulfate (9.45 g, 0.075 mol) was added over 5 minutes and the pH was maintained at 8-10 by the occasional addition of 5N sodium hydroxide solution. The solution is stirred for about 12 hours at room temperature and the insoluble material is filtered off. The paste-like solid was washed with cold water (2 x 50 mL) and dried in vacuo. 11.8 g of compound (3) are obtained. Yield 72%.

Example 3

Amidation of methyl 5-nitro-3- [N- (1,3,4-trihydroxytreo-but-2-yl)] carbamoylbenzoate (3) with ammonia and 5-nitro-3 [N- (1, Preparation of 3,4-trihydroxy-threobut-but-2-ylcarbamoyl] -benzamide (4) A solution of ester (3) (0.0305 mol) in methanol (50 ml) was added to the solution (20 ml, approximately 0.3 mol). concentrated ammonium hydroxide was added. The slurry was heated to 55-60 ° C for 30 minutes in a sealed reaction vessel. The reaction was found to be complete by TLC. Methanol and ammonium hydroxide were removed by distillation and replaced with water (50 mL). After cooling overnight, the insoluble product was filtered off and washed with cold water (2 x 50 mL). The product was dried in vacuo to give 7.15 g of a white amide (4). Yield 75%.

Example 4

Chlorination of 5-nitro-isophthalic acid monomethyl ester (1) with thionyl chloride and preparation of 5-nitro-isophthalic acid monomethyl ester monochloride (5)

Compound (1) (225 g, 1 mol) was dissolved in ethyl acetate (0.5 L) and N, N-dimethylformamide catalyst (0.1 mL) was added. The solution was heated to 70 ° C and 219 ml (3 mol) of thionyl chloride was added over 1.25 hours. The temperature was then maintained at 70 ° C for 2 hours.

Thionyl chloride was co-distilled with ethyl acetate (3 x 200 mL) and the product was dissolved in ethyl acetate (250 mL) and precipitated by addition of 11 cyclohexane. The precipitate was filtered off, washed with cyclohexane (2 x 200 mL) and dried at 50 ° C in vacuo. 216 g of compound (5) are obtained. 89% production.

Example 5

Amidation of 5-nitro-isophthalic acid monomethyl ester monochloride with amidooxepane and methyl-5-nitro-3- [N (trans-2,2-dimethyl-6-hydroxy-1,3-dioxepan-5-yl) Preparation of J-carbamoyl benzoate (6)

Monoester monochloride (5) (100 g, 0.411 mol) was dissolved in tetrahydrofuran (1 L) and solid amino-dioxepane (132.8 g, 0.825 mol) was added portionwise over 15 minutes. Meanwhile, the temperature was maintained below 25 ° C with an ice bath and the heterogeneous mixture allowed to stir for 30 minutes at room temperature. Thin layer chromatography indicated that the reaction was complete.

The insoluble amine hydrochloride was filtered off and the tetrahydrofuran was distilled off from the filtrate. The residue was dissolved in 400 ml of ethyl acetate at a temperature close to the boiling point, and the solution was allowed to stand for several days until the product crystallized. The solid was filtered off, washed with 2 x 50 ml of cold ethyl acetate and dried in vacuo. 82.4 g (6) of off-white product are obtained. Yield 55%.

Example 6

Amidation of methyl 5-nitro-3 - [N - (trans-2,2-dimethyl-6-hydroxy-1,3-dioxepan-5-yl) carbamoyl] -benzoate (6) with ammonium hydroxide and 5 Preparation of nitro-3 - [(N- (trans-2,2-dimethyl-6-hydroxy-1,3-dioxepan-5-yl) carbamoyl) -benzamide (7)

To a 800 mL Parr reactor was charged 80 g of compound (6) (0.22 mol), 110 mL of methanol, and 225 mL (3.38 mol) of 15N ammonium hydroxide. The reaction vessel was sealed and immersed in a 50 ° C water bath for 2 hours. TLC showed the reaction to be complete. The heterogeneous reaction mixture was mixed with 100 mL of water and the volatiles were distilled off to give a foamy residue. The foam material was suspended in 100 ml of water, filtered and washed with 2 x 50 ml of water. 60.4 g of white material (7) are obtained. Yield 79%.

Example 7

Reduction and deprotection of 5-nitro-3- [N- (trans-2,2-dimethyl-6-hydroxy-1,3-dioxepan-5-yl)] carbamoylbenzamide (7) on palladium on activated carbon and using hydrogen gas and hydrochloric acid and preparing 5-amino-hydrochloride -3- [N- (1,3,4-trihydroxytreo-but-2-yl)] carbamoyl-benzamide (8)

58 g (0.16 mol) of material (7), 410 ml of 1N hydrochloric acid and 5.8 g of palladium on charcoal (10% o Pd / C, 1 wt% Pd) were charged into a Parr reactor 1. The reaction vessel was connected to a source of hydrogen and shaken under 50 psi of hydrogen for 2 hours. HPLC showed a 90% conversion. The palladium catalyst is filtered off and the acetone formed during deprotection is distilled off under vacuum at 50 ° C. The resulting clear solution (450 ml, compound 8, 90% yield) was directly subjected to the iodination reaction.

Example 8

Iodination of 5-amino-3- [N- (1,3,4-trihydroxy-threo-but-2-yl) -carbamoyl] -benzamide hydrochloride (8) with iodine monoldoride and 5-amino-2,4-6 Preparation of triiodo-3- [N- (1,3,4-trihydroxytitreobut-2-yl) carbamoyl] benzamide (9)

A solution of the title compound (8) (0.14 mol) in 1N hydrochloric acid was heated to 85 ° C and 135 ml (0.49 mol) of iodine monochloride was added. The reaction mixture was heated to 85 ° C for 2 hours, after which time it was stirred under high pressure

According to another liquid chromatography analysis, the reaction is complete. The reaction mixture was cooled to 25 ° C and extracted with cyclohexane (2 x 200 mL), dichloromethane (3 x 300 mL) and chloroform (5 x 200 mL) until the purple material was removed from the aqueous phase. The resulting pale yellow solution was recycled through a column of 800 g Duolite-A340 and 266 g Dowex 50W-X8. The resin was washed with water (6 L) and the solution was concentrated to a volume of 300 mL, whereupon crystalline material began to precipitate. The product was filtered off to give 40 g of a white crystalline product (0.06 mol, 43% yield). MS: [M + H] + = 701.

Example 9

Acylation of 5-Amino-2,4,6-triiodo-3- [N- (1,3,4-trihydroxy-threobut-2-yl)] carbamoylbenzamide (9) with acetic anhydride and 5- (diacetylamino) Preparation of -2,4,6-triiodo-3- [N- (1,3,4-triacetoxy-threobut-2-yl) -carbamoyl] -benzamide (10) g of the title compound (9) (0.14). mole) was stirred at 70 ° C with 500 ml (4.95 mole) of acetic anhydride. 0.36 g (0.004 mol) of perchloric acid catalyst was added, causing the temperature to rise to 85 ° C. The reaction mixture was stirred for 1 hour at 85 ° C, when it became homogeneous, and TLC analysis showed the reaction was complete. Sodium acetate (0.33 g, 0.004 mole) was added to neutralize the perchloric acid and the solvent was evaporated to give a thick brown oily substance. The oily substance was diluted with 200 ml of ethyl acetate at 70 ° C and the solvent was removed. The distillation procedure was repeated twice to give a brown foam (10), 113 g, 0.13 mol, 93% yield).

Example 10

5- (Diacetylamino) -2,4,6-triiodo-3- [N- (1,3,4-triacetoxytitreobut-2-yl) carbamoyl] -benzamide (10) with sodium methoxide and deacetylation and alkylation with chloroethanol; and 5- [N- (2-hydroxyethyl) acetamido) -2,4,6-triiodo-3 [N- (1,3,4-trihydroxytreo-but-2) -yl) -carbamoyl] -benzamide (11)

To a solution of the title compound (10) (113 g, 0.13 mol) in methanol (500 ml) was added a solution of sodium methoxide 25% (55 g, 0.25 mol) at 50 ° C. After 5 hours, HPLC indicated the reaction to be complete and neutralized with 10 g Dowex 50W-X4 resin. The resin was filtered off and the filtrate was evaporated to a volume of 400 ml. The neutral methanolic solution was heated to 45 ° C and 129 g (0.34 mol) of trisodium phosphate and 18.2 ml (0.272 mol) of 2-chloroethanol were added. After stirring for 48 hours at 45 ° C, chloroethanol (4.7 ml, 0.07 mol) and sodium methoxide (14.7 g, 0.07 mol) were added. After 71 hours, HPLC indicated the reaction to be complete. The insoluble material (89 g) was filtered off and the solution was neutralized with 6N hydrochloric acid (7 mL). The solution was evaporated to give a brown foamy compound (11). 94 g (0.12 mol), 92% yield.

Mass Spectrum: (M + H) ⁺ = 748.

UV spectrum: λ = 205 nm, ε = 21,200, λ = 243 nm, ε = 29,500.

Example 11

Amidation of 5-nitro-isophthalic acid monomethyl ester (1) with 3-amino-1,2-propanediol and preparation of 5-nitro-3- [N- (2,3-dihydroxypropyl) carbamoyl] -benzoic acid (12)

225 g (1 mol) of the starting material (1) are mixed with 227.8 g (2.5 mol) of 3-amino-1,2-propanediol and heated to 110-120 ° C for 1 hour. The reaction is complete and the heterogeneous mixture is mixed with 1 L of water and 1.070 mL of concentrated hydrochloric acid. The mixture was cooled for several days to prevent complete precipitation of the product, and the precipitate was filtered off and washed with cold water (2 x 50 mL). The solid was dried in vacuo to afford 193 g (12%) (68%); mp 153-156 ° C.

UV spectrum: λ = 205 nm, ε = 25,300;

λ = 218ηπι, ε = 25,700;

λ = 247 nm, ε = 10,100;

Example 12

Reduction of 5-nitro-3- [N- (2,3-dihydroxypropyl)] - carbamoylbenzoic acid (12) in the presence of palladium on charcoal and 5-amino-hydrochloride -3- [N- (2, Preparation of 3-dihydroxypropyl) carbamoyl] -benzoic acid (13)

Nitric acid (12) (180 g, 0.634 mol) was mixed with water (11) and concentrated hydrochloric acid (60 ml), and palladium on charcoal (10%, 10%) was added. The suspension is hydrogenated at 2-4 atm until the hydrogen pressure remains constant. The reduction was then complete by HPLC and TLC. The catalyst was filtered off and the homogeneous filtrate was taken to the next step without isolation of the product. [(13), approximate yield 98%].

UV spectrum: λ = 220nm, ε = 25,000,

X = 326nm, ε = 2050.

Example 13

Iodination of 5-amino (hydrochloride) -3- [N- (2,3-dihydroxypropyl)] - carbamoylbenzoic acid (13) with iodine monochloride and 5-amino-2,4,6-triiodo-3- [N- Preparation of (2,3-dihydroxypropyl) carbamoyl] -benzoic acid (14)

A mixture of the starting material (13) (about 0.62 mol) in water (1.5 L) was diluted with water to a final volume of 4 L and then heated to 85 ° C. Thereafter, 499 ml (2.05 mol) of 4.1 molar iodine monochloride was added and the temperature was maintained at 90 ° C for 6-8 hours. The reaction is terminated by HPLC. The homogeneous mixture was cooled, extracted with 1 x 500 mL of 1,2-dichloroethane / cyclohexane (9: 1), then extracted with 2 x 250 mL of 1.2 dichloroethane. The aqueous phase is then evaporated to 0.91 volumes and cooled for several days to give a solid. The solid was filtered off, washed with water (2 x 100 mL) and dried in vacuo. 286 g (73% yield) of (14) are obtained; mp 148-150 ° C.

HU 219 585 Β

UV spectrum: λ = 231 nm, ε = 3000;

λ = 262ηηι, ε = 10,500;

λ = 320 nm, ε = 4900.

Example 14

Acetylation of 5-amino-2,4,6-triiodo-3- [N- (2,3-dihydroxypropyl) carbamoyl] -benzoic acid (14) with acetic anhydride and 5- (diacetylamino) -2,4,6- Preparation of triiodo-3- [N- (2,3-diacetoxypropyl) carbamoyl] -benzoic acid (15)

Starting material (14) (100 g, 0.158 mol) in acetic anhydride (300 ml, 3.16 mol) and 70% perchloric acid (0.2 ml) was heated at 80-90 ° C for 8 hours. The mixture was neutralized with 0.25 g of anhydrous sodium acetate and the acetic anhydride and acetic acid were distilled off at 70-80 ° C. The oily residue was azeotroped with 2 x 100 mL of ethyl acetate and then dissolved in 250 mL of ethyl acetate. The solution is directly subjected to a chlorination reaction. [(16) approximately 90% yield].

IR spectrum (KBr in pellet): 1770/1730 cm ^-1 (COOH); 1660 cm -1 (amide-CO); 1630 cm-1 (ester CO).

Example 75

Chlorination of 5- (diacetylamino) -2,4,6-triiodo-3- [N- (2,3-diacetoxypropyl)] carbamoylbenzoic acid (15) with thionyl chloride and 5- (diacetylamino) -2 Preparation of 4,6-triiodo-3- [N- (2,3-diacetoxypropyl) carbamoyl] -benzoyl chloride (16)

To a solution of the starting material (15) (1.142 mol) in ethyl acetate (225 ml) was added thionyl chloride (57 ml, 0.78 mol) at 65-70 ° C and the temperature was raised to 75-80 ° C for 1 hour. Thionyl chloride and ethyl acetate are then distilled off in vacuo. The residue was azeotroped with 2 x 100 mL of butyl acetate and dried in vacuo. The brown foamy material ((16), about 130 g, estimated yield 95%) was taken directly to the next amidation step. IR (Nujol): 1770/1730 cm ^-1 (COCl);

1630/1225 cm ^-1 (ester CO); 1600 cm -1 (amidCO).

Example 16

Amidation of 5- (diacetylamino) -2,4,6-triiodo-3- [N- (2,3-diacetoxypropyl)] carbamoylbenzoyl chloride (16) with ammonia and 5- (acetylamino) - Preparation of 2,4,6-triiodo-3- [N- (2,3-diacetoxypropyl) carbamoyl] -benzamide (17)

About 0.135 mol (16) of the acid chloride was dissolved in 150 ml of dry Ν, Ν-dimethylacetamide. The solution was cooled to 0-5 ° C and about 20 ml of anhydrous ammonia was condensed into the reaction mixture using a dry ice / acetone cooler. The reaction mixture was soldered and kept at room temperature for 24 hours. The ammonia and dimethylacetamide were removed by vacuum distillation. 500 ml of 1-pentanes are added to the residue and the precipitate is filtered off. The precipitate was washed twice with 150 ml of 1-pentanol and dried in vacuo. 82 g of compound 17 are obtained (80.2% yield).

Example 7

Deacetylation of 5- (acetylamino) -2,4,6-triiodo-3- [N- (2,3-diacetoxypropyl)] carbamoylbenzamide (17) and 5- (acetylamino) -2, Preparation of 4,6-triiodo-3- [N- (2,3-dihydroxypropyl) carbamoyl] -benzamide (18)

81.2 g (0.107 mol) of the title compound (17) are suspended in 203 ml of water and 16.9 ml (0.322 mol) of 50% w / w aqueous sodium hydroxide are added dropwise. The mixture was stirred and a clear solution was obtained. The solution was degassed in vacuo for 30 minutes and then 12 ml (0.18 mol) of hydrochloric acid (15 ml) was added. The mixture was then stored at 4 ° C and the precipitate formed was filtered off. The precipitate was washed with ice water (3 x 50 ml) and ethanol (80 ml). After drying in vacuo, 54.1 g of product (18) are obtained. 75% production. IR spectrum (KBr in pellet): 1670 cm <^-1> (amide-CO).

Example 18

Alkylation of 5- (acetylamino) -2,4,6-triiodo-3- [N- (2,3-dihydroxypropyl)] carbamoylbenzamide (18) and 5- [N- (2,3-dihydroxy) Propyl) acetamido] -2,4,6-triiodo-3- [N- (2,3-dihydroxypropyl) carbamoyl] -benzamide (19)

The title compound (39.7 g, 0.059 mol) was dissolved in a mixture of propylene glycol (16.7 ml), ethanol (120 ml) and 25% sodium methoxide (17.6 ml, 0.077 mol). Chloropropanediol (9.78 g, 0.0885 mol) was added and the mixture was stirred for 1 hour at 25 ° C. The reaction mixture was then heated to 33 ° C and stirred for a further 19 hours while adding 25% (w / w) sodium methoxide (3.4 mL, 0.015 mol). The reaction was quenched with 12M hydrochloric acid and concentrated in vacuo. Water (200 mL) was added to the residue and evaporated again. The resulting aqueous solution was deionized with Dowex 50 H ⁺ resin (62 g) and Duolite A-340 OH resin (140 g). The resins were eluted with water and the solution was evaporated. 150 g of a solution are obtained which are treated with 1.00 g of Norit Ultra SX activated carbon for 14 hours at 60 ° C. The activated carbon was filtered off and the resulting aqueous solution was stirred with 1.0 Dowex 50H ⁺ and 4 g Duolite A-340 OH for 2 hours. The resin was filtered off and the aqueous solution was evaporated. 50.3 g of an oily substance is obtained containing the desired product (19) (32.8 g, 74% yield) in glycerol / propylene glycol solution. This oil was purified by the procedure described in the next step.

Mass Spectrum: (M + H) + = 748.

Example 19

Peracetylation of 5- [N- (2,3-dihydroxypropyl) acetamido] -2,4,6-triiodo-3- [N- (2,3-dihydroxypropyl) carbamoyl] -benzamide (19) on a silica gel column purification followed by subsequent deacetylation

16.4 g (0.022 mol) of the title compound (19), diluted with 1.74 g (0.022 mol) of pyridine in 25.15 g of total glycerol / propylene glycol and 15 g (1.12 mol) of acetic anhydride, are added and the mixture is stirred for 18 hours. Heat to 60 ° C. The reaction mixture was then distilled in vacuo to an oil and the oily residue was dissolved in 100 ml of chloroform. The solution was washed twice with 50 ml of 0.1 N hydrochloric acid and then with 2 x 50 ml of 15% w / v brine.

HU 219 585 Β let it go. The chloroform layer was dried over magnesium sulfate, filtered and evaporated. The oily residue was purified by gradient elution on a silica gel column (900 g) eluting with 5% acetic acid-95% chloroform eluent to 5% acetic acid-4% methanol-91% chloroform. The purified fractions were combined and evaporated. The resulting foam was treated with 30 ml of methanol and 0.98 g (0.0054 mol) of 25% w / w sodium methoxide in methanol. After 30 minutes, the solution was evaporated and the residue was dissolved in methanol (20 mL) and stirred with Dowex 50 H ⁺ resin (1.3 g). When the pH drops from 12 to 5, the resin is filtered off and the solution is evaporated. The foamy residue was dissolved in water (25 mL) and the solution was evaporated. 8.12 g (49% yield) of (19) are obtained.

Example 20

Deacetylation of 5- (diacetylamino) -2,4,6-triiodo-3- [N- (2,3-diacetoxypropyl)] carbamoylbenzoic acid (15) and 5- (acetylamino) -2, Preparation of 4,6-triiodo-3- [N- (2,3-dihydroxypropyl) carbamoyl] -benzoic acid (20)

The title compound (15) (720 g, 0.9 mol) was dissolved in methanol (500 mL) and 25% sodium methoxide in methanol (345 mL, 1.5 mol) was added. The reaction mixture was stirred at 45-50 ° C for 4 hours and then concentrated in vacuo. The residue was acidified with 124 ml (1.5 mol) of 12M hydrochloric acid and the salts were filtered off. The filtrate was concentrated in vacuo and the resulting oil was dissolved in propanol (680 mL). The solution was cooled to 4 ° C and the product crystallized. The product (20) is filtered off, washed with propanol (2 x 300 ml) and dried in vacuo. 391 g (64%) of product are obtained.

Example 21

Alkylation of 5- (acetylamino) -2,4,6-triiodo-3- [N- (2,3-dihydroxypropyl)] carbamoylbenzoic acid (20) and 5- [N- (2,3-dihydroxy) Preparation of the sodium salt of propyl) acetamido] -2,4,6-triiodo-3- [N- (2,3-dihydroxypropyl) carbamoyl] -benzoic acid (21)

100 g (0.148 mol) of the title compound (20) are dissolved in 400 ml of methanol. To the solution was added 140.6 g (0.37 mol) of solid trisodium phosphate hydrate (Na ₃ PO ₄ 12 H ₂ O) followed by

Chloropropanediol (32.7 g, 0.296 mole) was added and 24.1 g (0.111 mole) of 25% w / w sodium methoxide in methanol was added dropwise. The reaction mixture was heated to 40 ° C for 10 hours, while additional 8.0 (0.0368 mol) of 25% (w / w) sodium methoxide in methanol was added. The salts were filtered off and the methanolic filtrate was acidified with 3.5 ml of 12M hydrochloric acid. The organic solution is concentrated on a rotary evaporator to give a thick oily product (21) which is taken directly to the next reaction step.

Example 22

Acetylation of 5- [N- (2,3-dihydroxypropyl) acetamido] -2,4,6-triiodo-3 [N- (2,3-dihydroxypropyl)] carbamoylbenzoic acid (21); - Preparation of [N- (2,3-diacetoxy-propyl) -acetamido] 2,4,6-triiodo-3- [N- (2,3-diacetoxy-propyl) -carbamoyl] -benzoic acid (22)

The starting material (21) (114 g, 0.148 mol) was mixed with pyridine (11.7 g, 0.148 mol) and acetic anhydride (605 g, 5.92 mol), and the mixture was stirred at 65-70 ° C for 2 hours. The mixture was evaporated and the oily residue was dried by azeotropic distillation with 2 x 100 ml of butyl acetate. The residue was then partitioned between water (300 mL) and toluene: ethyl acetate (3: 1, 200 mL). The aqueous phase was extracted with 3 x 100 mL of 3: 1 toluene / ethyl acetate and then acidified with 22.5 mL of hydrochloric acid in the presence of 300 mL of ethyl acetate. The acidic aqueous phase was separated and extracted with ethyl acetate (2 x 100 mL). The three ethyl acetate solutions were combined, dried over magnesium sulfate and filtered. The solvent was evaporated to give solid 22 (118 g, 87% yield).

Example 23

Chlorination of 5- [N- (2,3-Diacetoxy-propyl) -acetam] -J-2,4,6-triiodo-3- [N- (2,3-diacetoxy-propyl) -carbamoyl] -benzoic acid and 22 - Preparation of [N- (2,3-diacetoxy-propyl) -acetamido] -2,4,6-triiodo-3- [N- (2,3-diacetoxy-propyl) -carbamoyl] -benzoyl chloride (23)

The title compound (22) (113.6 g, 0.124 mol) was dissolved in ethyl acetate (100 ml), and thianyl chloride (44 g, 0.37 mol) was added dropwise at 55 ° C and the mixture was refluxed for 2 hours. The mixture was evaporated using a rotary evaporator and the residue was dried by azeotropic distillation with 2 x 50 ml of butyl acetate. The resulting foamy residue was dissolved in chloroform (200 mL) and the solution was 0.2M in 100 mL

Extract with pH 6.7 phosphate buffer. The organic phase is dried over magnesium sulfate, filtered and evaporated. 115 g (98% yield) of solid 23 are obtained.

Example 24

Amidation of 5- [N- (2,3-Diacetoxy-propyl) -acetamido] -2,4,6-triiodo-3- [N- (2,3-diacetoxy-propyl) -carbamoyl] -benzoyl chloride (23) and Preparation of 5- [N- (2,3-diacetoxy-propyl) -acetamido] 2.4.6-triiodo-3- [N- (2,3-diacetoxy-propyl) -carbamoyl] -benzamide (24)

To a solution of the title compound (23) (105 g, 0.111 mol) in acetonitrile (400 mL) was added dry ammonia at 25 ° C using a dry ice condenser. The mixture was refluxed for 3 hours. The reaction is complete. The salts are filtered off and the solution is concentrated. 98.8 g (96% yield) of (24) are obtained.

Example 25

Deacetylation of 5- [N- (2,3-Diacetoxy-propyl) -acetamido] -2,4,6-triiodo-3 [N- (2,3-diacetoxy-propyl)] - carbamoyl-benzamide (24); - Preparation of [N- (2,3-dihydroxypropyl) acetamido] 2.4.6-triiodo-3- [N- (2,3-dihydroxypropyl) carbamoyl] -benzamide (19)

Compound (24) (98.7 g, 0.16 mol) was dissolved in methanol (250 ml) and sodium methoxide (25% w / w in methanol, 2.30 g, 0.0106 mol) was added. The mixture was stirred for 15 minutes at 25 ° C and then concentrated in vacuo. The oily residue was treated with 200 ml of methanol 9

Dissolve the solution in Dowex 50 H + resin (6.0 g) until the pH changes from 12 to 6. The resin was filtered off and the solution was evaporated. The foamy residue was dissolved in 320 mL of water and refluxed with 3.0 g of Norit SX charcoal for 7 hours. The mixture was filtered and desalted with 3 g of Dowex 50 H ⁺ resin and 12 g of Dowex XUS-40123 OH resin. The mixture was filtered and evaporated. 79.2 g (96% yield) of solid product (19) are obtained.

Mass Spectrum: (M + H) ⁺ = 748.

Example 26

Methoxyacetylation of 5-amino-2,4,6-triiodo-3- [N- (1,3,4-trihydroxy-threobut-2-yl)] -carbamoyl-benzamide (9) with methoxyacetyl chloride and 5- Preparation of [(methoxyacetyl) amino] -2,4,6-triiodo-3- [N- (1,3,4-trihydroxy-threobut-2-yl) carbamoyl] -benzamide (25)

100 g (0.15 mol) of the title compound (9) (prepared according to Example 8) are suspended in 250 ml of N, N-dimethylacetamide at 25 ° C and 68 ml (0.75 mol) of methoxyacetate are added over 30 minutes. -acetyl chloride is added. The reaction mixture was stirred for 5 hours at 35 ° C, when the reaction was complete by HPLC. The reaction was quenched by the addition of 97 g (0.45 mol) of sodium methoxide and the mixture was stirred at 40 ° C for 2 hours. The solution was neutralized with Dowex 50W-X4 resin, filtered and diluted with 700 mL of butanol. The white precipitate was filtered off to give an off-white solid (25) (80.6 g, 73% yield, 0.11 mol).

Example 27

Alkylation of Ioxitalamic Acid (26) and 5- [N- (2,3-Dihydroxypropyl) Acetamido] -2,4,6-Triiodo-3- [N- (2-Hydroxyethyl) Carbamoyl] Sodium Benzoate (27) )

Ioxitalamic acid (266) (966 g, 1.5 mol) was dissolved in 1.5 L of 1N sodium hydroxide at room temperature, and the solution was heated to 75 ° C and 223.8 g (2.03 mol) in parallel over 1.25 hours. 3-Chloro-1,2-propanediol and about 0.4 L of 5N sodium hydroxide are added. The reaction mixture is heated to 80-90 [deg.] C. for 2.5 hours when the reaction is completed by HPLC (about 90%). conversion to product).

The reaction mixture was neutralized with about 3 mL of concentrated hydrochloric acid and concentrated. About half of the foamy residue is dissolved in 0.4 L of water. The solution is cooled and a white crystalline solid precipitates which is filtered off and washed with ice water. It was then dried to give 249 g of crystalline compound (27).

Example 28

Acetylation of 5- [N- (2,3-dihydroxypropyl) -acetam-time] -2,4,6-triiodo-3 [N- (2-hydroxyethyl) carbamoyl] sodium benzoate (27) and 5- [N- (2,3-diacetoxy-propyl) -acetamido) -2,4,6-triiodo-3- [N- (2-acetoxy-ethyl) -carbamoyl] -benzoic acid (28) g (0.067 mol) ) The title compound (27) was added at 25 ° C to 102 ml (1.080 mol, about 16.0 equivalents) of mixed acetic anhydride and 5.4 ml (0.067 mol, 1.0 equivalents) of pyridine was added. The temperature was heated to 85 ° C for 1 hour, when the reaction was complete by TLC. The homogeneous reaction mixture was evaporated in vacuo. The thick oily residue was dissolved in butyl acetate (50 mL) and evaporated again. The oily residue was dissolved in water (260 mL) and the solution was extracted with 2: 1 toluene / ethyl acetate (4 x 100 mL). The aqueous phase was acidified with 12N hydrochloric acid (11 mL) and extracted with ethyl acetate (3 x 50 mL). The organic layer was dried over magnesium sulfate and evaporated. Foam compound (28) (55 g, 0.065 mol, 97% yield) was obtained which was taken directly to the next step.

Example 29

Chlorination of 5- [N- (2,3-Diacetoxypropyl) acetamido] -2,4,6-triiodo-3- [N- (2-acetoxyethyl) carbamoyl] -benzoic acid (28) and 5- [ Preparation of N- (2,3-acetoxypropyl) acetamido] -2,4,6-triiodo-3- [N- (2-acetoxyethyl) carbamoyl] -benzoyl chloride (29) g (0.065 mol) 170 ml of the title compound (28)

Dissolved in 1,2-dichloroethane and heated to 85 ° C. Thionyl chloride (9.8 mL, 0.134 mol, 2.0 equiv.) Was added. The reaction was complete in 3 hours by TLC. The reaction mixture was concentrated in vacuo and the oily residue was dissolved in 50 ml of butyl acetate. The solution was evaporated again to give yellow foam (29) (51.9 g, 0.060 mol, 92% yield).

Example 30

Amidation of 5- [N- (2,3-Diacetoxy-propyl) -acetamido] -2,4,6-triiodo-3- [N- (2-acetoxy-ethyl)] - carbamoyl-benzoyl chloride (29); - Preparation of [N- (2,3-diacetoxypropyl) acetamido] 2,4,6-triiodo-3- [N- (2-acetoxyethyl) carbamoyl] benzamide (30)

The title compound (51) (51.9 g, 0.060 mol) was dissolved in acetonitrile (200 ml) and excess ammonia was added at 10 ° C. After 4 hours, TLC analysis indicated that the reaction was complete. The reaction mixture was filtered and the ammonium chloride salt was removed and the solvent was evaporated. 47 g (0.056 mol, 93% yield) of yellow oil (30) are obtained.

Example 31

Deacetylation of 5- [N- (2,3-Diacetoxy-propyl) -acetamido) -2,4,6-triiodo-3- [N- (2-acetoxy-ethyl) -carbamoyl] -benzamide (30) and 5- [ Preparation of N- (2,3-dihydroxypropyl) acetamido] -2,4,6-triiodo-3- [N- (2-hydroxyethyl) carbamoyl] -benzamide (31) g (0.056 mol) (30) To a solution of the title compound in 240 mL of methanol was added 3.9 g (about 0.3 equivalents) of 25% sodium methoxide and the pH was raised to about 12. The solution was stirred for 1 hour at 25 ° C, when deacetylation was complete by HPLC. The reaction mixture was treated with 10 ml of 1N hydrochloric acid 10

Neutralize with solvent and evaporate the solvent. 39 g (0.054 mol) of foam (31) are obtained (97% yield, 98% purity). Recrystallize 5 g of the product from 15 ml of hot methanol using seed crystals.

Example 32

Amidation of 5-amino-2,4,6-triiodo-isophthalic acid chloride (32) and preparation of 5-amino-2,4,6-triiodo-3- (chlorocarbonyl) -benzamide (33)

A solution of starting material (32) (300 g, 0.503 mol) in tetrahydrofuran (900 ml) was cooled to 5-10 ° C with an ice bath. Concentrated ammonium hydroxide solution (92.3 ml, 1.38 mol) was added over 10 minutes and the temperature was allowed to rise to 30 ° C.

The reaction mixture was stirred at room temperature for 90 hours while a total of 25.2 mL (0.38 mol) of ammonium hydroxide was added. The mixture was cooled and the precipitate was filtered off. The filtrate was washed with brine (2 x 200 mL).

The tetrahydrofuran was evaporated and the viscous oil was precipitated by addition of 800 ml of ethyl acetate. The brownish solid was filtered off, washed with ethyl acetate (2 x 100 mL) and dried. 193 g (66.5% yield) of 33 are obtained. Mass Spectrum: EI-576

Cl-584 (M + NH ₄ ) +.

Example 33

Dimerization of 5-amino-2,4,6-triiodo-3-chlorocarbonylbenzamide (33) and malonic acid bis [3- (chlorocarbonyl) -5-carbamoyl-2,4,6-triiodoanilide] Preparation 34 The title compound (33) (34.7 mmol) was dissolved in dry tetrahydrofuran (100 mL) and heated to 45 ° C. 2.53 ml (26 mmol) of malonyl dichloride are then added over 3 minutes. Dry tetrahydrofuran (100 mL) was added to the heterogeneous mixture and the suspension was stirred for 1 hour. TLC showed the reaction to be complete. The mixture was diluted with butyl acetate (150 mL) and the solid filtered. The solid was washed with butyl acetate (2 x 50 mL), dried in vacuo to give 13.18 g (34). 62% production.

Example 34

Amidation of bis [3- (chloro-carbonyl) -5-carbamoyl-2,4,6-triiodoanilide] (34) and malonic acid bis [3- (N) 1,3,4-trihydroxy-threobutyl] Preparation of 2-ylcarbamoyl] -5-carbamoyl-2,4,6-triiodoanilide (35)

Dissolve 8.0 g of the title compound (34) (6.56 mmol) in 10 ml of dry Ν, Ν-dimethylacetamide and add 1.83 ml (13.12 mmol) of triethylamine and cool to 20 ° C. . Trans-5-amino-2,2-dimethyl-6-hydroxy-1,3-dioxepane is added over 3 minutes and the homogeneous mixture is stirred at room temperature for 6 hours. TLC showed the reaction to be complete. The solvent was evaporated, water (50 ml) was added and the mixture was heated to 75 ° C for 15 minutes to decompose the acetonides. The product was isolated by evaporation and crystallization from 100 ml of isopropanol. The solid was washed with isopropanol (2 x 20 mL), dried and dried

8.6 g of compound 35 are obtained. 94% production.

Example 35

Amidation of 5- (N-methylamino) -2,4,6-triiodoisophthaloyl chloride (36) and 5- (N-methylamino) -2,4,6-triiodo-3- (chlorocarbonyl) - Production of benzamide (37)

The starting material (305 g, 36) (0.5 mol) was dissolved in tetrahydrofuran (1 L) and cooled to 10 ° C. Concentrated ammonium hydroxide (100 mL, 1.5 mol) was added over 5 minutes. The temperature rises to 25 ° C.

The mixture was stirred at room temperature for 65 hours while conc. Ammonium hydroxide (3.5 ml) was added after 20 hours and 3.5 ml (44 ml) was added after 44 hours.

The mixture was cooled and the bisamide precipitated was filtered off and the filtrate was washed with brine (2 x 100 mL).

The tetrahydrofuran was evaporated and the resulting oily product was crystallized from ethyl acetate (500 mL). The solid was filtered off, washed with ethyl acetate and dried. 132.1 g (37) are obtained in 45% yield.

Example 36

Dimerization of 5-N-methylamino-2,4,6-triiodo-3- (chlorocarbonyl) benzamide (37) and bis [3- (chlorocarbonyl) -5-carbamoyl-2,4-malonic acid, Preparation of 6-triiodo-N-methylanilide] The title compound (38) (38) (42.3 mmol) was dissolved in dry tetrahydrofuran (100 mL) and the homogeneous solution was heated to 50 ° C. 3.05 ml (31.2 mmol) of malonyl dichloride was added over 2 minutes, then another 50 ml of tetrahydrofuran was added and the resulting suspension was heated for 1 hour. TLC showed the reaction to be complete.

The mixture was diluted with 50 ml of butyl acetate and the precipitate was filtered off. The precipitate was washed with butyl acetate (2 x 25 mL) and dried. 15.24 g of product (38) are obtained. Off-white solid. 58% production.

Example 37

Conversion of malonic acid bis [(3-chlorocarbonyl-5-carbamoyl) -2,4,6-triiodo-N-methylanilide (38) to malonic acid bis [3-N (1,3,4-trihydroxy] Threo-2-butylcarbamoyl) -5-carbamoyl / 2,4,6-triiodo-N-methylanilide] (39) g (8 mmol) of starting material (38) was dissolved in 15 ml of dry Ν, Ν- dimethylacetamide and 2.23 mL (16 mmol) of triethylamine. Trans-5-amino-2,2-dimethyl-6-hydroxy-1,3-dioxepane (aminodioxepane) (3.22 g, 20 mmol) was added over 5 minutes, and the homogeneous mixture was stirred for 8 hours, then TLC analysis. indicates completion of the reaction.

The dimethylacetamide is removed by vacuum distillation and the isopropylidenes are decomposed with aqueous hydrochloric acid at 50 ° C. The water was removed in a rotary evaporator and isopropanol was added to precipitate the product. Filtration, washing with isopropanol (3 x 10 mL) and drying afforded dimer (39) (9.86 g, 87%).

HU 219 585 Β

The structure of the dimer is determined from its analytical and spectroscopic data.

A Büchi apparatus is used to determine the uncorrected melting point. The R _r value was measured by TLC on Merck pre-coated silica gel (6OF254) 0.2 mm thick aluminum sheets. Infrared spectra were recorded on a Nicolet FT-IR 205 spectrometer with potassium bromide pellet. The α and ¹³ C NMR spectra were measured on a Brucker AC-200 spectrometer using d ₆ -dimethylsulfoxide as the solvent. Chemical shifts (δ) of the λ-NMR spectrum are reported in ppm, below the trimethylsilane. Chemical shifts in ¹³ C-NMR spectra are based on solvent and the assignments listed are based on DEPT experiments. The mass spectrum was recorded as FAB + (L-SIMS).

Melting point: 280 ° C (dec) _(H2O)

R _f = 0.54 (n-BuOH-AcOH-H ₂ O, 3: 2: 1), (UV detection).

IR spectrum (potassium bromide in pastilles): 3395,

3324,3201,1647,1527,1040 cm '. 1 H-NMR (d ₆ -dimethylsulfoxide) δ:

2.85-3.20 (m, 6H, CH ₃ ), 3.50-3.90 (m, 12H, CH ₂ ,

CH), 4.44-4.87 (m, 6H, OH), 7.73-8.06 (m, 6H,

NH, NH ₂ ).

Δ ¹³ C-NMR (d ₆ -dimethyl sulfoxide):

170.91, 169.20, 165.39, 164.95 (CO-N), 151.60,

151.18, 150.56, 148.75, 146.18 (Ar), 98.03, 97.65,

92.26, 91.46, 90.56 (Ar-I), 69.03, 68.80 (CH),

63.46 (CH ₂ ), 58.79 (CH ₂ ), 52.40, 52.08 (CH),

42.73 (CH ₂ ), 37.06, 33.61 (CH ₃ ).

Mass Spectrum (FAB +) m / z 1418.7 (M ⁺ + H).

Example 38

Conversion of 5-N- (Methyl) amino-2,4,6-triiodo-3- (chlorocarbonyl) benzamide (36) to 5- [N- (methyl) -2-acetoxyacetamido] -2,4,6- To triiodo-3- (chlorocarbonyl) -benzamide (40), the starting material (36) (40) (42.3 mmol) was dissolved in dry N, N-dimethylacetamide (50 mL). To the solution was added 2-acetoxyacetyl chloride (6.83 mL, 63.5 mmol) and stirred overnight. TLC indicated the reaction to be complete.

The product was precipitated by adding 200 ml of ice water. The precipitate was filtered off, washed with water and dissolved in 200 ml of tetrahydrofuran. The solution was washed with 250 mL of a 3: 1 mixture of saturated sodium chloride solution and saturated sodium bicarbonate solution, followed by 100 mL of saturated sodium chloride solution. The organic layer was dried over magnesium sulfate and the solvent removed to give 22.1 g (77.2%) of a foamy title product (40).

Example 39

5- (N-Methyl-2-hydroxy-acetamido) -2,4,6-triiodo-3- [N (1,3,4-trihydroxy-threo-but-2-yl) -carbamoyl] -benzamide (41 ) by amidation of 5- (N-methyl-2-acetoxyacetamido) -2,4,6-triiodo-3- (chlorocarbonyl) -benzamide (40) and deprotection

Compound 40 (7.0 g, 10.35 mmol) was dissolved in a mixture of tetrahydrofuran (40 mL) and triethylamine (1.44 mL, 10.35 mmol) and the solution was cooled to 10 ° C. Solid amino dioxepane (2.0 g, 12.41 mmol) was added, the cooling bath was removed and the reaction mixture was stirred at 25 ° C. After 18 hours, TLC analysis indicated that the reaction was complete. The reaction mixture was diluted with 40 mL of tetrahydrofuran and 50 mL of saturated brine: saturated sodium bicarbonate (3: 1). The layers were separated and the organic layer was washed with 2x40 mL of brine. The organic solution was dried over magnesium sulfate and evaporated. 6.9 g of a foamy product are obtained. 82% production,

The foam was dissolved in 50 mL of methanol and 0.5 mL of 4.6 N sodium methoxide was added. The solution was evaporated at 50 ° C and the resulting oily substance was mixed with 50 ml water and 10 g Dowex 50 H ⁺ resin. The mixture was heated to 60 ° C for 30 minutes to give a homogeneous solution. HPLC analysis showed ester and isopropylidene cleavage.

The resin was filtered and the solution was circulated on a Duolite A 340 OH ^- and Dowex 50 H ⁺ column until deionized. The compound was eluted from the columns with water. Then 0.4 g of Norit Ultra SX activated carbon is treated.

After stirring for 1 hour at 70 ° C, the charcoal is filtered off and the water is evaporated. White foamy compound (41) was obtained, 3.8 g, 50% yield based on material (40).

Example 40

Acetoxyacetylation of 5-amino-2,4,6-triiodo-3- (chlorocarbonyl) benzamide (33) and 5- (acetoxyacetylamino) -2,4,6-triiodo-3- (chloro) -carbonyl) -benzamide (42)

A solution of 200 g (0.347 mol) of starting material (33) in 1200 ml of dioxane is heated to 60 ° C. To the solution, 142 g (1.041 mol) of acetoxyacetyl chloride was added dropwise over 15 minutes. The reaction mixture was then

Stir at 90 ° C for 6.5 h. The mixture was cooled to 15 ° C and the precipitated solid (42) was filtered. The precipitate was washed with 4 x 100 mL of diol, dried in vacuo to give 200.5 g (85% yield).

Example 41

Amidation of 5- (acetoxyacetylamino) -2,4,6-triiodo-3- (chlorocarbonyl) benzamide (42) and 5- (acetoxyacetylamino) 2,4,6-triiodo-3- Preparation of [N- (2,3-dihydroxypropyl) carbamoyl] -benzamide (43)

118 g (0.174 mol) of starting material (42) are combined with 180 ml of N, N-dimethylacetamide, 24.2 g (0.266 mol) of 3-amino-1,2-propanediol and 180.0 g (0.177 mol) of triethylamine. The reaction mixture was stirred for 4 hours at 25 ° C. The mixture was then diluted with 1080 ml of pentanol dropwise with vigorous stirring. The precipitate (43) was filtered off, washed with pentanol (4 x 100 mL) and dried in vacuo. 124.5 g (98% yield) of crude product are obtained.

HU 219 585 Β

Example 42

Deacetylation of 5- (acetoxyacetylamino) -2,4,6-triiodo-3- [N- (2,3-dihydroxypropyl)] carbamoylbenzamide (43) and 5- (hydroxyacetylamino) Preparation of -2,4,6-triiodo-3- [N- (2,3-dihydroxypropyl) carbamoyl] -benzamide (44)

The starting material (43) (124.2 g, 0.170 mol) was dissolved in a mixture of methanol (1.5 L) and water (0.5 L) and treated with Dowex 50 H + and Biore 5 OH ion exchange resin. After stirring for 20 hours, the resins were filtered off and the resulting mixture was concentrated in vacuo. 400 ml of methanol and 36.9 g (0.17 mol) of 25% w / w sodium methoxide in methanol are added to the solid residue. The resulting solution was filtered and the methyl acetate was evaporated in vacuo. The mixture was then diluted with methanol, neutralized with concentrated hydrochloric acid and concentrated in vacuo. A solid is obtained which contains 9.9 g of NaCl and 940.0 g of (44). Yield 80%.

Example 43

Reaction of 5- (hydroxyacetylamino) -2,4,6-triiodo-3- [N- (2,3-dihydroxypropyl)] carbamoylbenzamide (44) with 3,4-dihydro-2H-pyran and 5- (2-Tetrahydropyranyloxyacetylamino) -2,4,6-triiodo-3- [N- (2,3-ditetrahydropyranyloxypropyl] carbamoyl] -benzamide (45)

The starting material (44) (3.44 g, 5 mmol) was treated with dioxane (15 mL) and methanesulfonic acid (29.5 mg, 0.31 mmol). To the mixture was added 3.36 g (40 mmol) of 3,4-dihydro-2H-pyran, followed by stirring at 25 ° C for 4 days. The mixture was filtered, made basic by the addition of triethylamine (62 mg, 0.62 mmol) and evaporated in vacuo. The resulting oily residue is dissolved in methanol and concentrated in vacuo to give a residue (45) which is directly subjected to an alkylation reaction.

Example 44

Alkylating and then deprotecting 5- (2-tetrahydropyranyloxyacetylamino) -2,4,6-triiodo-3- [N- (2,3-ditetrahydropyranyloxypropyl)] carbamoylbenzamide (45); Preparation of 5- [N- (2-hydroxyethyl) hydroxyacetamido] -2,4,6-triiodo [3- (2,3-dihydroxypropyl) carbamoyl] -benzamide (46) ), the semi-solid crude product obtained in the previous step was treated with 18 ml of methanol, 4.75 g (12.5 mmol) of trisodium phosphate decahydrate and 805 g (10 mmol) of chloroethanol. The suspension was stirred at 40-45 ° C for 31 hours, then filtered and diluted with 0.5 mL of concentrated hydrochloric acid. The acidic filtrate was concentrated in vacuo. The oily residue was dissolved in 20 mL of 0.01 N hydrochloric acid and 20 mL of methanol was added. This was repeated twice and the acidic solution was again evaporated. Solid 3.50 g (46) is obtained. 95% production.

Example 45

Alkylation of 3,5-Diacetylamino-2,4,6-triiodobenzoic acid (47) with sodium 3,5- [N, N '- (2,3-dihydroxypropyl) diacetamido] -2,4 Preparation of 6-triiodobenzoate (48) for a suspension of g (0.079 mol) of starting material (47) in 300 ml of methanol: 149 g (0.393 mol) of trisodium phosphate dodecahydrate and 35 g (0.314 mol) of 3-chloro-1,2 -propanediol is added. The mixture was heated to <RTIgt; C </RTI> for 24 hours and the insoluble material was filtered off under vacuum. The filtrate was neutralized with hydrochloric acid and concentrated. White foam (48) (about 59 g, containing 10% ester by-product) was obtained. Yield 94%. The product is directly subjected to an acetylation reaction.

Example 46

Acetylation of sodium 3,5- [N, N '- (2,3-dihydroxypropyl) diacetamido] -2,4,6-triiodobenzoate (48) and 3,5- [N, N' (2) Preparation of 3-Diacetoxy-propyl) -diacetamido] -2,4,6-triiodobenzoic acid (49) g (0.075 mol) (48) starting material 150 ml (1.58 mol) acetic anhydride and 6 ml (0.075 mol) Pyridine solution was heated to 85 ° C for 1 hour. Acetic anhydride, acetic acid and pyridine are then distilled off at 70-80 ° C and the yellow foamy residue is azeotroped with 2 x 50 ml of butyl acetate.

The product (sodium salt of compound 49) was dissolved in water (300 mL) and extracted with toluene / ethyl acetate (3: 150 mL, 2: 1). Thus, the ester by-product formed in the previous alkylation step is removed. The aqueous solution was then acidified to pH 2.5 with concentrated hydrochloric acid and the precipitate was extracted with ethyl acetate (2 x 75 mL). The combined organic solution was dried over magnesium sulfate and the solvent was evaporated. About 58 g of yellow oil (49) are obtained. Yield: 83% based on compound (47). The product is directly subjected to a chlorination reaction.

Example 47

Chlorination of 3.5- [N, N '- (2,3-diacetoxypropyl) diacetamido] -2,4,6-triiodobenzoic acid (49) and 3,5- [N, N' - (2,3-diacetoxy) -propyl) -diacetamido] -2,4,6-triiodobenzoyl chloride (50)

To a solution of the starting material (49) (about 0.062 mol) in ethyl acetate (125 ml) was added thionyl chloride (23 ml, 0.32 mol) at 65-70 ° C and the temperature at 75-80 ° C for 1 hour. lift. TLC showed the reaction to be complete. The thionyl chloride and ethyl acetate were distilled off in vacuo and the residue azeotroped with 2 x 150 mL of butyl acetate. The resulting solid was dried. The foamy material ((50), about 56 g, 95% yield) was taken directly to the next amidation step.

Example 48

Amidation of 3.5- [N, N '- (2,3-diacetoxypropyl) diacetamido] -2,4,6-triiodobenzoyl chloride (50) and 3,5- [N, N' - (2,3-diacetoxy) propyl) diacetamido] -2,4,6-triiodobenzamide (51)

To a solution of about 0.059 mol (50) of the starting material in 200 ml of acetonitrile was added anhydrous ammonia at 10 ° C. The temperature was raised to 25 ° C for 5 hours. The reaction was completed by TLC analysis. The ammonium chloride was filtered off and the filtrate was evaporated. Yellow foam (51) (53 g, estimated yield 97%) was obtained. The foam material is directly subjected to the deacetylation reaction.

HU 219 585 Β

Example 49

Deacetylation of 3,5- [N, N '- (2,3-diacetoxypropyl) diacetamido] -2,4,6-triiodobenzamide (51) and 3,5- [N, N' - (2,3-dihydroxy) propyl) diacetamido] -2,4,6-triiodobenzamide (52)

A solution of material (51) (0.057 mol) in methanol (250 ml) was added to a solution of sodium methoxide (5.0 g, 0.023 g) in methanol (4.6 g). The mixture was stirred at room temperature for 30 minutes, when deacetylation was complete by TLC analysis. The reaction mixture was neutralized with concentrated hydrochloric acid and the insoluble sodium chloride was filtered off. The filtrate was evaporated. 43 g (52) of a yellow foam are obtained. Yield: 97%; purity by HPLC: 98%.

Example 50

Preparation of malonic acid bis [3-N- (2,3-dihydroxypropylcarbamoyl) -5-carbamoyl] -2,4,6-triiodo-N- (2,3-dihydroxypropyl) Janilide

A) Preparation of 5-Amino-2,4,6-triiodo-3- (chlorocarbonyl) benzamide

To a suspension of 5-amino-2,4,6-triiodoisophthalamic acid (53.0 g, 0.1 mol) in ethyl acetate (265 ml) was added thionyl chloride (21.9 ml, 0.3 mol) and the mixture was heated to reflux. hours. The reaction was quenched by the addition of water (6 mL) and the solvent was distilled off to almost dryness. The residue was filtered, washed with ethyl acetate and dried in vacuo; 47 g (80%) of the title pure acid chloride are obtained.

IR spectrum (in potassium bromide pellet): 3450,

3305, 1770, 1680, 1661, 1589, 1389, 1021 δ CMA * H NMR (D ₆ -dimethyl sulfoxide):

3.5 (bs, 2H, Ar-NH ₂ ), 7.6-8.1 (m, 2H,

Ar-CONH ₂ ).

Δ ¹³ C-NMR (d ₆ -dimethyl sulfoxide):

171.62, 171.15, 170.19, 169.82 (CO); 151.35,

149,67,149,61,148,02,147,61,143,71 (Ar); 98.52.

96.75, 89.18, 80.44, 78.44, 72.36 (Ar-I).

B) Preparation of N, N'-Bis [3- (chlorocarbonyl) -5-carbamoyl-2,4,6-triiodophenyl] malononamide

A suspension of 45.0 g (0.078 mole) of the acid chloride prepared in Step A in 135 ml of dry dioxane is heated to 90 ° C and 4.6 ml (0.047 mole) of malonyl chloride is added with vigorous stirring. After stirring for 45 minutes, the mixture was cooled to room temperature, the resulting solid filtered off, washed with dioxane and dried in vacuo.

Yield: 38.5 g (80%).

IR (potassium bromide in pastilles): 3166,

1778,1654,1514,1359 cm -1.

1 H-Nuclear magnetic resonance spectrum (d ₆ -dimethylsulfoxide) δ:

3.5 (s, 2H, CH ₂ ), 7.7-8.3 (m, 4H, CONH ₂ ),

10.2-10.5 (m, 2H, CONH).

¹³ C-NMR (in d ₆ -dimethylsulfoxide) δ: 171.09,

170.62, 169.82, 169.67, 168.46, 164.88, 164.75, (CO); 151.54, 150.93, 149.43, 149.13, 143.87,

143.71, 143.06, 142.89 (Ar); 102.47, 99.23, 97.40,

96.08, 88.51, 87.06 (Ar-I); 42.80 (CH ₂ ).

C) Preparation of N, N'-Bis {5-carbamoyl-3- [N - [(2,3-isopropylidenedioxy) propyl] -carbamoyl] -2,4,6-triiodophenyl} malononamide

30.0 g (0.025 mol), 11.5 g (0.108 mol) of anhydrous sodium carbonate and 9.1 g (0.054 mol) of 2,2-dimethyl-5- (aminomethyl) -1,3 of dioxan hydrochloride in 200 ml of ethyl acetate was heated to reflux for 48 hours. During this time, the reaction is complete and the resulting solid is filtered off, washed with water and dried in vacuo.

Yield: 32 g (85%).

IR (potassium bromide in pastilles) 3252, 3185, 1685, 1669, 1652, 1540, 1503, 1370, 1352, 1213 cm ^-1 .

^! 1 H NMR (d ₆ -dimethylsulfoxide) δ: 1.26 (s, 6H, CH ₃ ), 1.35 (s, 6H, CH ₃ ), 3.1-3.5 (m, 4H , CH ₂ -N), 3.34 (s, 2H, OC-CH ₂ -CO), 3.7-4.1 (m, 4H, CH ₂ O), 4.1-4.3 (m, 2H, CH-O),

7.6-8.1 (m, 4H, Ar-CONH ₂ ), 8.5-8.8 (m, 2H, Ar-CONH), 10.2 (broad s, 2H, CONH-Ar).

¹³ C NMR (d ₆ -dimethylsulfoxide) δ: 171.16, 169.83, 165.02 (CO); 150.63, 149.77, 143.31 (Ar); 108.53 (carbon atom of isopropylidene fragment); 98.52, 89.46 (Ar-I); 73.30 (CH-O); 67.72 (CH ₂ -O); 42.02 (CH ₂ y CH ₂ N); 27.10 (CH ₃ ); 25.52 (CH ₃ ).

D) Preparation of bis [malonic acid bis [3-N- (2,3-dihydroxypropylcarbamoyl) -5-carbamoyl] -2,4,6-triiodo-N- (2,3-dihydroxypropyl) anilide

A mixture of 34.0 g (0.024 mol) of the compound prepared in Step C and 43.4 g (0.114 mol) of trisodium phosphate decahydrate in 170 ml of methanol is heated to 50 ° C and added at this temperature.

8.7 ml (0.104 mol) of 3-chloro-1,2-propanediol and the mixture was stirred for 48 hours. During this time, the reaction is complete, the mixture is cooled to room temperature, the inorganic salts are filtered off and the filtrate is evaporated to dryness in vacuo. The residue was slurried with water, filtered again and dried.

Yield: 35 g (92%) of N, N'-bis (2,3-dihydroxypropyl) -N, N'-bis {5-carbamoyl-3- [N - (2,3-isopropylidenedioxy) propyl] / carbamoyl] -2,4,6-triiodo-phenyl} malonamide. This compound was dissolved in 200 mL of a 1: 1 mixture of methanol and water and treated with concentrated hydrochloric acid at pH 1 at 50 ° C for 5 hours. The reaction mixture was then neutralized to pH 6.5 and evaporated to dryness in vacuo. The resulting residue was purified by preparative liquid chromatography (PLC) in reverse phase eluting with a mixture of methanol and water. The purest fraction collected was evaporated to dryness in vacuo to give 22 g (60%) of the pure title compound having an internal code number of ICI 3393.

Melting point: 257 ° C (dec) _(H2O).

_Rf value: 0.36 (n-BuOH-AcOH-H ₂ O, 3: 2: 1) (detection by UV light).

IR spectrum (potassium bromide in pastilles): 3388,

3300, 1666, 1645, 1557, 1400, 1286, 1036 cm-1

HU 219 585 Β

1 H-NMR (d ₆ -dimethylsulfoxide) δ:

2.6-4.0 (m, 22H, CH ₂ , CH), 4.4-4.9 (m, 8H, OH), 7.3-8.9 (m, 6H, CONH, CONH ₂ ) .

¹³ C NMR (d ₆ -dimethylsulfoxide) δ: 171.71, 171.40, 171.10, 169.92, 167.24, 166.95, 166.17, (CO-N); 151.47, 148.21, 147.02 (Ar); 101.04, 100.79, 100.04, 98.61, 91.66, 90.11 (Ar-I); 69.97 (CHOH); 64.68, 64.06, 63.15 (CH ₂ OH);

54.10 (CH ₂ -NAr); 42.63 (NOC-CH ₂ CON, CON-CH ₂ ).

Mass spectrum (FAB +) m / z 1479.1 (M + + H).

Example 51

A solution for injection containing 5- [N- (2,3-dihydroxypropyl) acetamido] -2,4,6-triiodo-3- [N- (2,3-dihydroxypropyl) carbamoyl] -benzamide (19) was formulated. shape

Ingredients of 100 ml solution Solution for injection in mg / ml iodine 300 350 400 Active ingredient (g) 58.87 68.68 78.49 Ethylenediaminetetraacetic acid, disodium, calcium salt (mg) 10 10 10 Tris (hydroxymethyl) aminomethane (mg) 121 121 121 Water for injection (ml) 100 100 100 Osmolality (mOsm / kg) 399 473 510 Viscosity 37 ° C (centipoise) 4.1 6.6 10.6

Procedure: Ethylenediaminetetraacetic acid disodium, calcium salt, tris (hydroxymethyl) aminomethane and contrast medium were dissolved in water for injection and adjusted to pH 7.0 with 1N hydrochloric acid. The solutions were made up to 30 ml with water for injection, injected into vials on a 0.22 μm membrane, sealed and autoclaved at 121 ° C for 20 minutes.

Example 52

5- [N- (2-hydroxyethyl) acetamido] -2,4,6-triiodo-3- [N- (l, 3,4-trihydroxy-threo-but-2-yl) carbamoyl] benzamide (11)

Ingredients of 100 ml solution Solution for injection in mg / ml iodine 300 350 400 Active ingredient (g) 58.87 68.68 78.49 Ethylenediaminetetraacetic acid, disodium, calcium salt (mg) 56 56 56 Trisodium citrate (mg) 77 77 77 Water for injection (ml) 100 100 100 Osmolality (mOsm / kg) 301 337 370 Viscosity at 37 ° C (centipoise) 4.2 6.6 13.1

Procedure: Dissolve the ethylenediaminetetraacetic acid disodium, calcium salt, trisodium citrate, and contrast medium in water for injection. Adjust the pH of the solution to 5.0-6.0 with sodium carbonate and carbon dioxide. The solution is made up to 100 ml with water for injections. The solution is injected into vials using a 0.22 μ membrane filter. The vials were sealed and autoclaved for 20 minutes at 121 ° C.

It will be apparent from the description of the method of the invention that the nonionic contrast agent produced has advantages over previously known such materials. Although many contrast agents have been prepared and tested, the compounds of the present invention have proven to be superior. The compounds of the present invention contain three different nitrogen atoms, only two of which are substituted, resulting in a preferred

EN 219 585 Β. Furthermore, the production process yields high yields and uses readily available starting materials.

The process of the invention has been described in detail for the sake of clarity, but it will be apparent to those skilled in the art that the process can be modified without modifying the spirit of the invention, and these modifications are within the scope of the invention.

Claims (14)

PATENT CLAIMS 1. Nonionic contrast agents of the formula I, containing at least 2 hydroxyl groups per molecule, wherein: R 1 is hydrogen, R ₂ is hydroxy (C 2 -C 6 alkyl) wherein the number of hydroxyl groups is 1- (nl) and n is the number of carbon atoms, R4 is hydrogen or alkyl of 1 to 6 carbon atoms, optionally substituted with up to η-1 hydroxy, wherein n is the number of carbon atoms, R ₃ is (C 1 -C 6) alkyl, (C 1 -C 6) hydroxyalkyl, or (C 1 -C 6) alkoxy (C 1 -C 6) alkyl, or R ₃ is a group of formula (a) wherein R _b R ₂ and R 4 are as defined above, 3- [N- (1,3-dihydroxy-2-propyl) -carbamoyl] -5 - [(2-hydroxy) Except 1-oxopropyl) amino] -2,4,6-triiodobenzamide. A nonionic contrast agent according to claim 1, wherein R _{2 is} substituted with 4 carbon atoms and 3 hydroxy groups, R ₃ is other than a group of formula (a), and R 4 is substituted with 2 or 3 carbon atoms and at least 1 hydroxy group. . A nonionic contrast agent according to claim 1, wherein R _{2 is} substituted with 3 carbon atoms and 2 hydroxy groups, R ₃ is other than a group of formula (a) and R _{4 is} substituted with 3 carbon atoms and 2 hydroxy groups. 4. non-ionic contrast medium according to claim 3, characterized in that R ₂ and R ₄ are identical groups. 5- [N- (2-hydroxyethyl) acetamido] -2,4,6-triiodo-3- [N- (1,3,4-trihydroxytreo-2-butyl) according to claim 1 ) karbamoilj benzamide. The 5- [N- (2,3-dihydroxypropyl) acetamido] -2,4,6-triiodo-3- [N- (2,3-dihydroxypropyl) carbamoyl] of claim 1. benzamide. The 5- [N- (2,3-dihydroxypropyl) acetamido] -2,4,6-triiodo-3- [N- (2-hydroxyethyl) carbamoyl] benzamide according to claim 1 . The 5- [N-methyl-2-hydroxyacetamido] -2,4,6-triiodo-3- [N- (1,3,4-trihydroxytreo-2-butyl) carbamoyl according to claim 1 benzamide. The malonic acid bis [3- [N- (1,3,4-trihydroxytreo-2-butyl) carbamoyl] -5-carbamoyl-2,4,6-triiodo-N-methylanilide according to claim 1] . The 5- [N- (2-hydroxyethyl) hydroxyacetamido] -2,4,6-triiodo-3- [N- (2,3-dihydroxypropyl] carbamoyl] -benzamide according to claim 1. 11. A process for the preparation of nonionic contrast agents of the formula I wherein at least 2 hydroxy groups are present and wherein R 1 is hydrogen, R ₂ is hydroxy (C 2 -C 6 alkyl) wherein the number of hydroxyl groups is 1- (nl) and n is the number of carbon atoms, R 1 is hydrogen or C 1-6 alkyl optionally substituted with up to n-1 hydroxy groups, wherein n represents the number of carbon atoms, R ₃ is (C 1 -C 6) alkyl, (C 1 -C 6) hydroxyalkyl, or (C 1 -C 6) alkoxy (C 1 -C 6) alkyl, or R ₃ is a group of formula (a) wherein R _b R ₂ and R ₄ are as defined above, 3- [N- (1,3-dihydroxy-2-propyl) -carbamoyl] -5 - [(2-hydroxy) except for -1-oxopropyl) aminol-2,4,6-triiodobenzamide, characterized in that a) a compound of formula V wherein R and R ₂ is as defined herein and the hydroxy group (s) in R ₂ optionally contain a protecting group (s) - in a catalytic solvent, preferably pyridine, dimethylacetamide or dimethylformamide, with a compound of formula R ₃ COX wherein X is a halogen atom or an ester residue - with a strong base, compounds of formula (I) ₄ is hydrogen R optional protecting group (s) present are removed and, if desired, R ₄ is other than hydrogen (I ) a compound of formula with an alkylating agent of, if desired, salifying a compound having protective group (s) R is ₄ groups under basic conditions applied to an alkylation reaction, the resulting R, other than hydrogen ₄ is a general vegyületb (I) wherein substituents of material round the formula l optional protecting group (s) present are removed, or b) a compound of formula VI wherein R ₅ is hydrogen, R ₆ is R ₂ or hydrogen, X is halogen or ester residue, with ammonia, or R ₆ is a hydroxy containing R ₂ ; alkylamine, the hydroxyl group (s) of which may optionally contain a protecting group (s), and the optional group (s) is removed. 12. Radiological compositions comprising a nonionic contrast agent of the formula (I) containing at least two hydroxy groups per molecule, wherein: HU 219 585 Β Rj is hydrogen, R ₂ is hydroxy (C 2 -C 6 alkyl) wherein the number of hydroxyl groups is 1- (nl) and n is the number of carbon atoms, R4 is hydrogen or alkyl of 1 to 6 carbon atoms, optionally substituted with up to 5 η-1 hydroxy groups, n being the number of carbon atoms, R ₃ is (C 1 -C 6) alkyl, (C 1 -C 6) hydroxyalkyl, or (C 1 -C 6) alkoxy (C 1 -C 6) alkyl, or R ₃ is a group of formula (a) wherein R 1, R ₂ and R ₄ are as defined above, 3- [N- (1,3-dihydroxy-2-propyl) -carbamoyl] -5 - [(2- other than hydroxy oxopropylamino) -2,4,6-triiodobenzamide, together with a physiologically acceptable carrier. 13. The radiological composition of claim 12, which is 5- [N (2-hydroxyethyl) acetamido] -2,4,6-triiodo-3- [N- (1,3, 4-trihydroxy-threo-2-butyl) -carbamoyl] -benzamide. 14. The radiological composition of claim 12 wherein the compound of Formula I is 5- [N- (2,3-dihydroxypropyl) acetamido] 2,4,6-triiodo-3- [N- (2,3-dihydroxypropyl) carbamoyl] benzamide.